The present invention relates to certain novel anti-diarrheal and gastrointestinal anti-spasmodic agents and methods of treatment and pharmaceutical compositions based thereon.
Diarrhea can result from a variety of pathophysiological disorders including bacterial and parasitic infections, disease or debilitation of organs such as liver, adrenal and others. It can also occur as a result of other therapy or diet. In all cases, diarrhea is generally a symptom of organic gastrointestinal disorders and not itself a disorder. Chronic diarrhea is generally due to: (1) hypersecretion of fluid and electrolytes of the stomach, small intestine and colon; (2) inability to absorb certain nutrients (malabsorption); and (3) intestinal hypermotility and rapid transport. These may occur separately or in combination. Certain disorders may have diarrhea as a prominent feature of the disease/syndrome, but the specific etiology is unclear. In this latter group, emotional tension and psychological factors may adversely influence the frequency of the symptoms.
Diarrhea and diarrheal diseases are one of the most frequent causes of morbidity and mortality, especially in less developed countries wherein the number of those killed by such diseases is estimated at about 5 million persons per annum. Particularly dangerous are diarrheal diseases of the newborn and the youngest group of babies (S. Hughes: Drugs, Vol. 26, pp. 80-90 (1983)).
In mechanized or automated large capacity farms, diarrhea and infections of the gastrointestinal tract are frequent, especially with young livestock and the high mortality or growth deceleration thereof have a considerable negative economical effect. Diarrheal diseases of man and animals are caused by a plurality of etiological factors, especially of microbial and viral character. The most prevalent microbes are gram-negative bacteria, Escherichia coli and Vibrio cholerae. However, it is now clear that other bacteria, viruses and parasites (protozoan, amoeba, etc.) also cause severe problems.
Diarrheal diseases are treated by rehydration therapy using preparations composed of various salts (potassium chloride, sodium chloride, sodium hydrogen carbonate) and glucose, whereby quick compensation for the loss of water and ions, as well as for acidosis, occurs. However, the occurrence of diarrheal diseases is not influenced. Other substances of the same kind produce similar results.
Anti-diarrheal compounds are, of course, well known in the medicinal arts and take various forms. In particular, there are a variety of products known which act systemically to provide anti-diarrheal effects when administered in a manner which will enable the drug to be taken into the system at effective therapeutic levels.
In addition, there are anti-cholinergic substances applied together with spasmolytics such as Reasec. RTM. (Janssen) which contain diphenyloxylate and atropin. Both human and veterinary medicine use chemotherapeutic agents with anti-bacterial effects, such as sulfonamides, or antibiotics are availed of which are apt to suppress certain infections.
Medicaments are also aimed at the sphere of regulation depending on receptors, especially those localized on the basolateral membrane, further by means of an intracellular mechanism of intervention by the so-called secondary messenger, and by influencing the transport mechanism, especially boundary membranes. The modulation of receptor-dependent regulation mechanisms can be influenced, to some extent, by medicaments of the type alpha.sub.2 adrenergic agonists such as clonidine (Catapresan.RTM.) (E. B. Chang et al, Gastroenterology, Vol. 91, pp. 564-569 (1986)), somatostatin, or encephalin and morphine analogs. For influencing the transport of ions through the membrane, it is also possible to use alpha.sub.2 adrenergic agonists (E. B. Chang et al, Am. J. Physiol., Vol. 1982, p. 242). Reference has also been made to the use of lidamidine, i.e., the medicament having a damping effect on the intestine peristaltics (M. D. Dharmsathphom: Gastroenterology, Vol. 91, pp. 769-775 (1986)).
Disadvantages of anti-diarrheal medicaments, i.e., those referred to in professional papers rather than those medicaments of this type applied in practice, include their secondary strong effects such as antihypertensive effects (clonidine), growth factors (somatostatin), habituation and/or incomplete preclinical research (encephalin derivatives). The application of large doses of antibiotics and long administration thereof has not proved optimum in epidemical diarrhea localities. Where the diarrhea-inducing agent is cholera toxin, however, there does not exist any efficient protection, exception for inoculum which is not sufficiently potent either, and gives short-term protection only (3 months) and low efficiency (30-40%).
In recent years, a great deal of attention has been focused on the polyamines, e.g., spermidine, norspermidine, homospermidine, 1,4-diaminobutane (putrescine) and spermine. These studies have been largely directed at the biological properties of the polyamines probably because of the role they play in proliferative processes. It was shown early on that the polyamine levels in dividing cells, e.g., cancer cells, are much higher than in resting cells. See Janne et al, A. Biochim. Biophys. Acta., Vol. 473, p. 241 (1978); Fillingame et al, Proc. Natl. Acad. Sci. U.S.A., Vol. 72, p. 4042 (1975); Metcalf et al, J. Am. Chem. Soc., Vol. 100, p. 2551 (1978); Flink et al, Nature (London), Vol. 253, p. 62 (1975); and Pegg et al, Polyamine Metabolism and Function, Am. J. Cell. Physiol., Vol. 243, pp. 212-221 (1982).
Several lines of evidence indicate that polyamines, particularly spermidine, are required for cell proliferation: (i) they are found in greater amounts in growing than in non-growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth. Despite this evidence, the precise biological role of polyamines in cell proliferation is uncertain. It has been suggested that polyamines, by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules such as nucleic acids by anion neutralization. See Dkystra et al, Science, Vol. 149, p. 48 (1965); Russell et al, Polyamines as Biochemical Markers of Normal and Malignant Growth (Raven, New York, 1978); Hirschfield et al, J. Bacteriol., Vol. 101, p. 725, (1970); Hafner et al, J. Biol. Chem., Vol. 254, p. 12419 (1979); Cohn et al, J. Bacteriol., Vol. 134, p. 208 (1978); Pohjatipelto et al, Nature (London), Vol. 293, p. 475 (1981); Mamont et al, Biochem. Biophys. Res. Commun., Vol. 81, p. 58 (1978); Bloomfield et al, Polyamines in Biology and Medicine (D. R. Morris and L. J. Morton, eds., Dekker, New York, 1981), pp. 183-205; Gosule et al, Nature, Vol. 259, p. 333 (1976); Gabbay et al, Ann. N. Y. Acad. Sci., Vol. 171, p. 810 (1970); Suwalsky et al, J. Mol. Biol., Vol. 42, p. 363 (1969); and Liquori et al, J. Mol. Biol., Vol. 24, p. 113 (1968).
However, regardless of the reason for increased polyamine levels, the phenomenon can be and has been exploited in chemotherapy. See Sjoerdsma et al, Butterworths Int. Med. Rev.: Clin. Pharmacol. Thera., Vol. 35, p. 287 (1984); Israel et al, J. Med. Chem., Vol. 16, p. 1 (1973); Morris et al, Polyamines in Biology and Medicine; Dekker, New York, p. 223 (1981); and Wang et al, Biochem. Biophys. Res. Commun., Vol. 94, p. 85 (1980).
It has been previously reported that diethylhomospermine (DEHSPM) inhibited myoelectric activity and transit of the small intestine in rats [J. Gastro. Motil., Vol. 1, p. 53 (1989)]. This inhibition was reversed with co-administration of bethanechol, a cholinergic agonist, but not with other agonists or antagonists [Gastro., Vol. 98, p. A388 (1990)]. However, there is no suggestion or disclosure in the prior art that any of the above-described polyamines have utility as anti-diarrheal or gastrointestinal anti-spasmodic agents.
Recently, it has been found that certain polyamines function effectively as anti-diarrheal and gastrointestinal anti-spasmodic agents. See U.S. Pat. Nos. 5,393,757 and 5,462,970, the entire contents and disclosures of which are incorporated herein by reference. See also Bergeron et al, J. Med. Chem, Vol. 39, pp 2461-2471 (1996); which discloses that certain hydroxy-substituted polyamines are effective anti-diarrheal agents.
In a series of studies, Tansy was able to demonstrate that polyamines have a profound impact on the motility of the gastrointestinal (UI) tract. The original work focused on poly(ethylenimine) and gastric emptying in rodents and dogs. Branched-chain poly(ethylenimine)s effected significant inhibition of gastric emptying in rodents; however, they caused a severe retch response in dogs. Because of the structural relationship between the poly(ethylenimine)s and natural polyamines, Tansy elected to evaluate the effect of spermidine, spermine, and a group of polyamine analogues on the gastric emptying of rodents. It soon became clear that polyamines had a substantial influence on gastric emptying and that xe2x80x9cendogenous spermine and spermidine may have some unrecognized GI secretomotor activityxe2x80x9d. [See Spermine and Spermidine as Inhibitors of Gastrointestinal Motor Activity, Surg. Gyn. Obst, 1982, 154, 74-80; Pharmacology of Polyethylenimine I:Effects on Gastric Emptying In Rats, J. Pharm. Sci. 1977, 66. 899-901; GI Pharmacology of Polyethylenimine II: Motor Activity in Anesthesthetized Dogs, J. Pharm Sci. 1977, 66,902-904; Effects of Spermine and Spermidine on Gastric Emptying in Rats, J. Pharm. Sci 1981, 70 347]. From a structure-activity perspective, it also became obvious that minor changes in the polyarnine""s structure could completely eradicate the molecule""s ability to inhibit gastric emptying. These studies strongly suggested that the polyarnine pharmacophore was an excellent candidate for the construction of antitransit, antidiarrheal drugs.
One polyamine analogue designed and synthesized by the present inventor, N1, N14 diethylhomospermine (DEHSPM), is a very potent antidiarrheal. This has been demonstrated in a number of animal models and, in the clinic against AIDS-related diarrhea. However, DEHDSPM is N-deethylated to homospermine (HSPM), which has a very protracted half life: 2-3 weeks in mice and even longer in the dog. Each succeeding dose of DEHSPM results in a further accumulation of HSPM until toxic levels of the latter tetraamine are reached, a troublesome metabolic property in animals. [See Structural Specificity of Synthetic Analogues of Polyamines and their Effect on Gastrointestinal Motility, Polyamines and the Gastrointetinal Tract, Falk Symposium, NO. 62; Kluwer Academic: Boston, 1991; Potent Anti-Diarrheal Activity of a New Class of Compounds: Synthetic Analogues of the Polyamine Pathway. Gastroenterology 1993, 104, A54; J. Metabolism and Pharmacokinetics of N1, N14-Diethylhomospermine. Drug Metab. Dispos. 1996, 24, 334-843].
It is an object of the present invention to provide novel anti-diarrheal and gastrointestinal antispasmodic pharmaceutical, compositions and methods of treatment based upon certain polyamines other than those described in the prior art as effective therefor.